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Nature. 2016 Feb 18;530(7590):349-53. doi: 10.1038/nature16939. Epub 2016 Feb 10.

Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid.

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Institute of Neuroimmunology, Institute for Multiple Sclerosis Research, University Medical Centre Göttingen, 37073 Göttingen, Germany.
Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
Department of Structural and Geotechnical Engineering, University of Rome La Sapienza, 00185 Rome, Italy.
Department Neurosurgery, University Medical Centre Göttingen, 37075 Göttingen, Germany.
Division of Immunology, Department of Pediatrics Dalhousie University, Halifax B3H 4R2, Canada.
Departamento de Biología Celular e Inmunología, Centro de Biología Molecular Severo Ochoa, 28049 Madrid, Spain.
Medical Clinic and Policlinic IV, Ludwig-Maximilians-University of Munich, 80336 Munich, Germany.
Department of Neurology, University Hospital, 01307 Dresden, Germany.
Max-Planck-Institute for Experimental Medicine, 37075 Göttingen, Germany.


In multiple sclerosis, brain-reactive T cells invade the central nervous system (CNS) and induce a self-destructive inflammatory process. T-cell infiltrates are not only found within the parenchyma and the meninges, but also in the cerebrospinal fluid (CSF) that bathes the entire CNS tissue. How the T cells reach the CSF, their functionality, and whether they traffic between the CSF and other CNS compartments remains hypothetical. Here we show that effector T cells enter the CSF from the leptomeninges during Lewis rat experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. While moving through the three-dimensional leptomeningeal network of collagen fibres in a random Brownian walk, T cells were flushed from the surface by the flow of the CSF. The detached cells displayed significantly lower activation levels compared to T cells from the leptomeninges and CNS parenchyma. However, they did not represent a specialized non-pathogenic cellular sub-fraction, as their gene expression profile strongly resembled that of tissue-derived T cells and they fully retained their encephalitogenic potential. T-cell detachment from the leptomeninges was counteracted by integrins VLA-4 and LFA-1 binding to their respective ligands produced by resident macrophages. Chemokine signalling via CCR5/CXCR3 and antigenic stimulation of T cells in contact with the leptomeningeal macrophages enforced their adhesiveness. T cells floating in the CSF were able to reattach to the leptomeninges through steps reminiscent of vascular adhesion in CNS blood vessels, and invade the parenchyma. The molecular/cellular conditions for T-cell reattachment were the same as the requirements for detachment from the leptomeningeal milieu. Our data indicate that the leptomeninges represent a checkpoint at which activated T cells are licensed to enter the CNS parenchyma and non-activated T cells are preferentially released into the CSF, from where they can reach areas of antigen availability and tissue damage.

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